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Meloxicam is variably claimed by Boehringer
Ingelheim to be the First Generation of Selective COX 2- Cyclooxygenase
Enzyme Inhibitors.
However it is NOT a specific COX
2 drug and inhibition of COX 1 occurs at its therapeutic concentration - causing the same
overall profile of side effects
as seen with the other conventional non steroidal anti-inflammatory drugs
(NSAIDs). Only Celecoxib and Rofecoxib can claim true specificity. Meloxicam is
NOT a COXIB class drug. It is now available in the
USA, but in my opinion must be seen as an old fashioned NSAID that belongs with
the group of NSAIDs associated with classical COX 1 side effects of Gastropathy
and effects on platelets and kidneys.
The COX1 - constitutive form performs the housekeeping
functions responsible for physiological prostaglandin production especially
in the Gastric, mucosa and Kidney. Inhibition of this produces side affects
of Non-steroid Anti-inflammatories.
The other isoform - COX2 is induced by inflammatory
mediators and has a role in inflammation. Inhibition of this is responsible
for the therapeutic effects of Non-steroidal Anti-inflammatories.
Therefore, selective Non-steroidal Inhibiting
COX2 - relative to COX1 theoretically retained anti-inflammatory action,
but minimized the harmful side affects of those drugs. Until this time,
Misoprostol in combination with anti-inflammatories has been the only recognized
form of protection against gastropathy.
Large differences have been established in respect
of anti-inflammatories and relative potencies against COX1 and COX2. Hence,
the pharmaceutical industry searched to find a truly selective COX2 Inhibitor,
whilst preserving COX1.
A symposium was held in 1995 at EULAR and that
symposium is reviewed here.
The gathering is published in the Scandinavian
Journal of Rheumatology - 1996, Volume 25, Supplement 102.
The symposium was introduced by Dr James Fries.
-
Dr Fries in the paper titled "Toward an
Understanding of NSAID Related Adverse Effects - The Contribution of Longitudinal
Data Looks at the ARAMIS - Arthritis, Rheumatism and Ageing Medical Information
System Statistics.". This looks at 1 700 subjects from 17 Centers in the USA. Looking at data from the general population - approximately,
3% of deaths are related to gastro-intestinal events. When looking at Rheumatoid
Arthritis patients, that figure is approximately 6% - suggesting an excess
death rate of approximately 3%.
The GI deaths attributable to Non-steroids
represent approximately 0.1% per year.
Extrapolating such data to the USA suggests that
there are 2600 gastro-intestinal mediated deaths annually caused by Non-steroidals
in Rheumatoid Arthritis patients.
Risk Factors are identified - Including:
Age
Use of Prednisone
Higher anti-inflammatories doses
Disability index.
Ranking order for side affects have identified
certain anti-inflammatories to be worse than others and a GI Toxicity index
was also looked at.
| In rank order: |
DRUGS |
GI Toxicity index |
| 1. |
Salsalate |
0.871 |
| 2. |
Aspirin |
1.06 |
| 3. |
Ibuprofen |
1.16 |
| 4. |
Sulindac |
1.63 |
| 5. |
Naproxen |
1.78 |
| 6. |
Piroxicam |
2.07 |
| 7. |
Tolmetin |
2.16 |
| 8. |
Diclofenac |
2.17 |
| 9. |
Indomethacin |
2.40 |
| 10. |
Fenoprofen |
2.48 |
| 11. |
Ketoprofen |
3.09 |
| 12. |
Meclofenamate |
4.03 |
Disease Modifying Anti-Rheumatic Drugs
(DMARD),
were looked at in a similar way:
|
RANK
|
DRUGS
|
TOXICITY
|
| 1. |
Hydroxychloroquine |
1.38 |
| 2. |
Intra-muscular Gold |
2.27 |
| 3. |
Penicillamine |
3.38 |
| 4. |
Methotrexate |
3.82 |
| 5. |
Azathioprine |
3.92 |
| 6. |
Auranofin |
5.25 |
This suggests that the DMARDs are not as toxic
as what was once felt and this has important implications regarding the
traditional use of Non-steroidals and Disease Modifying Anti-Rheumatic
Drugs in the treatment of Rheumatoid Arthritis. This would appear to justify
the aggressive approach in using such DMARDs early.
John Vane and R Botting - "Mechanism of Action
of Anti-inflammatory Drugs" The whole
pathway of the Prostaglandin System and Cyclooxygenase is reviewed here
- as is the discovery of the second Cyclooxygenase Enzyme - COX2.
In the article, he discusses the possibility of
a Third Cyclooxygenase - COX3 which he considers as possibly in the brain
and for which selective antagonists have yet to be found. Differences between
anti-inflammatories regarding the Inhibition of COX1 and COX2 are identified.
The higher potency against COX1 than COX2 is expressed
as a ratio of the IC50 Values
- so that a higher COX2 to COX1 ratio indicates more potent inhibition
of COX1. The IC50 represent the concentration
required to produce 50% Inhibition of COX activity.
|
NSAID’s
|
COX2-IC50
|
COX1-IC50
|
RATIOCOX2 TO COX1
|
| Piroxicam |
0.6 ± 0.2 |
0.0024 ± 0.0006 |
250 |
| Diclofenac |
1.1 ± 0.47 |
1.57 ± 0.66 |
0.7 |
| Indomethacin |
1.68 ± 0.2 |
0.028 ± 0.0028 |
60 |
| Naproxen |
5.65 ± 9.57 |
9.56 ± 4 |
0.6 |
| Ibuprofen |
72.8 ± 25.9 |
4.58 ± 0.3 |
15 |
| Sulindac |
112 ± 65 |
1.12 ± 0.78 |
100 |
| Aspirin |
278 ± 55 |
1.67 ± 1.11 |
166 |
Of note, the lower the IC50 Value for COX1
- the less the drug concentration required to inhibit COX1 and this is
seen for example., with Piroxicam - where you have a high COX2 to COX1
ratio - suggesting a very low selectivity.
Of note, is that the Diclofenac COX1 IC50 is 1.57
and the Ration is 0.7 - suggest that this is one of the more ideal existing
anti-inflammatory.
The IC50 Studies are all in vitro studies and
the ratios can vary according to the types of cell used and whether the
tests are done instantaneously or on incubation and thus several different
values for the same compound may be quoted depending of the biological
system on which the tests were done.
Accurate comparisons of the selectivity of the
drugs are only possible with a standard test designated for measuring inhibitory
potential for the 2 isoenzymes.
In a study done by Engelhardt et al in the
Journal Inflammatory Research 1995, Volume 44, Pages 422 - 433.
He does a comparative study looking at different
anti-inflammatory drugs COX2 IC50 and the COX1 IC50 and Ratio of COX2 to
COX1.
| NSAIDs |
COX-2IC50
micromol/litre |
COX1-IC50
micromol/litre |
RATIOCOX2 TO COX1 |
| Meloxicam |
0.0019 |
0.00577 |
0.33 |
| Diclofenac |
0.0019 |
0.000855 |
2.2 |
| Piroxicam |
0.175 |
0.00527 |
33 |
| Tenoxicam |
0.322 |
0.201 |
15 |
| Indomethacin |
0.00636 |
0.00021 |
30 |
| Tenidap |
47.8 |
0.393 |
122 |
The source of cells were Peritoneal Macrophages
from Guinea Pigs.
Clearly, the COX2 to COX1 Ratio of Diclofenac
is extremely favorable. Of note, is that the COX1 IC50 for Meloxicam is
0.00577.
The application of different test systems to measure
COX selectivity is a great cause of confusion and are in fact not directly
comparable in different studies. So conclusion regarding the relative activity
of a Non-steroidal against COX1 and COX2 are likely to be flawed if the
COX2 to COX1 Ratios are obtained from different sources.
Absolute values of COX2 to COX1 Ratios from different
systems should not be directly compared - however, the rank order of COX
selectivity for a range of compounds, seems to be broadly reproducible
from system to another.
Whilst Meloxicam may be favorably ranked regarding
the COX2 Ratio, the IC50 of SC58125 was 0.09 and over a 100 micro mol for
COX1 - making it 1400 more selective for COX2. Even at greater than anti-inflammatory
doses, did not inhibit prostaglandin synthesis in the stomach and does
not cause gastric ulceration.
SC 58635 - celecoxib (Searle) has an approximate
COX2 to COX1 ratio of 325-fold.
What are my conclusions therefore:-
Clearly, the lower the IC50 for COX1, the less
amount of drug required that will produce this effect. Hence, it is important
to know the concentration of Meloxicam, measured in micromol, since- if
this concentration is greater than the IC50 dose - then there is COX1 inhibition
irrespective of the actual ratio of COX2 to COX1.
This problem is not seen with SC58125 which has
a IC50 for COX1 of 100 micromol, and its COX2 to COX1 Ratio is over 1 400.
The agent however is not currently being further developed.
SC 58635 - celecoxib also does not seem to show
significant inhibition of COX1, and is currently in phase 3 trials, with
release projected for approximately 1999.
The plasma concentrations are below the IC50 for
the COX1 system, and hence - the housekeeping system remains intact.
Therefore, it is important to analyze
a review of the Pharmacokinetics of Meloxicam and this is reviewed
by Turck et al. from British Journal of Rheumatology - 1996, Volume 35,
Supplement 1 - Pages 30 - 60.
Meloxicam is an Enolic
class NSAID drug and its tolerability is believed to be due to the preferential
inhibition of COX2 over COX1.
The Pharmacokinetic characteristics of Meloxicam
have been extensively investigated and Plasma concentration - Time Profiles
have been obtained from more than 400 male and female volunteers in the
study. The drug was administered by intravenous or Intramuscular solution
as well as oral administrations.
The absorption was investigated and Plasma concentration
- Time Profiles at steady state are illustrated in the Paper. The absorption
of Meloxicam is independent of dose over the range 7.5 to 30mg leading
to dose linear increases in Meloxicam - Plasma concentrations.
Most of the drug is bound to Albumin - greater
than 99% and there is a restricted volume of distribution - it is predominantly
distributed to higher perfused compartments - such as the blood, liver
and kidney’s. It rapidly penetrates other tissues. 40 - 45% of the accompanying
steady state Meloxicam Plasma Concentrations are found in Synovial fluid.
It is eliminated by Metabolic Degradation with equal renal and faecal elimination
and has a half life of 20 hours. Steady state concentrations are achieved
within 3 - 5 days.
The Plasma C-max (Maximal plasma concentrations)
after multiple doses range from 0.88 - 1.05mg/litre at 7.5mg and from 1.92
to 2.45mg/litre for 15mg doses. Since the molecular weight of Meloxicam
is 351g/mol - the Plasma concentration after Meloxicam 7.5mg can be calculated
from C-max 0.88 using a molecular weight of 351g/mol to represent 2.51 micromol- which is well above the IC50 for COX1 - making the Ratio actually
irrelevant here. At C-max 1.05mg/litre using molecular weight of 351g/mol
- the Plasma concentration is 2.10 micromol. At 15mg dose C-max is 1.92 mg/litre representing a concentration of 5.47micromol and the maximal C-max
of 2.45 at 15mg dosing is 6.98 micromol.
Therefore, at standard Meloxicam dosing
of 7.5mg to 15mg. The concentration of drug in the Plasma far exceeds the
IC50 levels that therefore, suggest that COX1 inhibition will take place.
This makes the claim of being a true COX2 selective inhibitor to be potentially
untrue.
It has come to my notice that the claim of COX2
selectivity has been challenged in various European Centers and that in
Sweden, the claim of selectivity has been disputed and permission for registration
as such has been questioned.
In conclusion,
true COX2 Selectivity - COX 2
specificity
- remains valid only for 2 drugs
available - Celecoxib and Rofecoxib. (Celebrex and Vioxx).
My feeling is that Meloxicam has only slightly improved
COX 2
Ratios compared to Diclofenac and that its protective factor regarding
gastropathy reflects this, but it is by no means a truly COX2 Selective
Inhibitor (in my own personal opinion).
Diclofenac is an anti-inflammatory with similar COX1/2 ratios and provides a reasonable rank order profile.
Misoprostol remains the only registered indication for prevention of gastropathy.
Combination with misoprostol reduces
ulcers and gastropathy by a further 60 %.
Numerous studies exist to confirm this - with
reduction compared to Diclofenac (already relatively favorable COX2 Ratio)
from 11.1% to 4.4% when compared as a study of Diclofenac versus arthrotec
(Diclofenac-Misoprostol combination)
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